The present invention relates to a method for producing a 2-alkyl-2-cyclopentenone useful as a synthetic intermediate of a biologically active substance or a perfume as well as a method for producing a jasmonate derivative useful as a perfume material or a biologically active substance by using the same.
As a method for producing a 2-alkyl-2-cyclopentenone, for instance, there is a method which comprises obtaining a 2-alkylidene cyclopentanone by dehydrating reaction of a 2-(1-hydroxyalkyl)-cyclopentanone and then isomerizing this 2-alkylidene cyclopentanone. Among such a method, there is known a method for producing a 2-alkyl-2-cyclopentenone by bringing a hydrogen halide into contact with a 2-alkylidene cyclopentanone and there are also investigated variable improvements thereof (JP-A 59-80625 etc.).
In this method, however, it is impossible to obtain the product in a high yield without low concentration condition so that further improvements have been desired for industrial production. As this improved method therefor, there is also known a method using a hydrogen halide salt of an amine in place of the above-mentioned hydrogen halide (JP-A 6-80606). Even in this method, however, no sufficiently satisfactory yield can be obtained without adding a solvent in excess.
Further, those methods wherein a 2-(1-hydroxyalkyl)-cyclopentanone is dehydrated and isomerized at one stage are also known (JP-A 56-147740 and JP-A.5-92934). However, these methods have drawbacks such as longer reaction time, poor yield, much solvent and poor productivity.
JP-A 51-23240 discloses a method for producing a 2-alkyl-2-cyclopentenone with a hydrogen halide or sulfonic acid.
The object of the present invention is to provide a method for efficiently producing a 2-alkyl-2-cyclopentenone as well as a method for producing a jasmonate derivative by using the same.
The present invention relates to a method for producing a 2-alkyl-2-cyclopentenone represented by the formula (2) (referred to hereinafter as the compound (2)): 
wherein each of R1 and R2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 8 carbon atoms, or R1 and R2 may be formed into a cyclopentane or cyclohexane ring together with a bonded carbon atom, which comprises reacting an amine and a hydrogen halide with a 2-alkylidene cyclopentanone represented by the formula (1) (referred to hereinafter as the compound (1)) at a molar ratio of the amine/the hydrogen halide of from 1.1/1 to 5/1 to carry out isomerization reaction: 
wherein R1 and R2 have the same meanings as defined above, as well as it relates to a method for producing the compound (2), which comprises reacting a catalyst comprising an amine and a hydrogen halide with a 2-(1-hydroxyalkyl)-cyclopentanone represented by the formula (3) (referred to hereinafter as the compound (3)) to carry out dehydration-isomerization reaction: 
wherein R1 and R2 have the same meanings as defined above.
Further, the present invention relates to a method for producing a jasmonate derivative represented by the formula (5) (referred to hereinafter as the compound (5)): 
wherein R1 and R2 have the same meanings as defined above, R3 represents a linear or branched alkyl group having 1 to 3 carbon atoms, which comprises reacting the compound (2) obtained in the method described above with a malonic acid diester represented by the formula (4) (referred to hereinafter as the compound (4)): 
wherein R1 , R2 and R3 have the same meanings as defined above, and the two R3 groups may be the same or different, and then reacting water therewith.
Furthermore, the present invention also provides use of the 2-alkyl-2-cyclopentenone obtained by the method described above as an intermediate for a jasmonate derivative.
[Method 1: The Method for Producing the Compound (2) Obtained from the Compound (1)]
The compound (1) used in the present invention can be produced by a publicly known method in the conventional art. For example, it can be easily synthesized by a method for condensing an enamine of cyclopentanone with an aldehyde and then decomposing the dehydrated-condensed product with an acid; a method of dehydrating the compound (3); or the like.
The compound (1) includes 2-butylidene cyclopentanone, 2-(2xe2x80x2-methylbutylidene) cyclopentanone, 2-pentylidene cyclopentanone, 2-hexylidene cyclopentanone, 2-cyclopentylidene cyclopentanone, 2-cyclohexylidene cyclopentanone and 2-(1xe2x80x2-methylbutylidene)-cyclopentanone.
The amine and hydrogen halide used in the present method at are reacted at a molar ratio of the amine/the hydrogen halide of from 1.1/1 to 5/1, preferably 1.2/1 to 3/1 and more preferably 1.5/1 to 3/1 in order to obtain the compound (2) in a high yield even in a small amount of a solvent.
The amine used in the present method is preferably a weakly basic aromatic amine or heterocyclic aromatic amine. Specifically, there may be exemplified aniline, diphenylamine, pyridine, picoline, quinoline and polyvinyl pyridine. Pyridine, picoline or quinoline is particularly preferable. The hydrogen halide may be hydrogen chloride, hydrogen bromide or hydrogen iodide. Hydrogen chloride or hydrogen bromide is particularly preferable.
The amine and hydrogen halide may be previously mixed at the ratio described above having the excess amine in order to use the mixture. On the other hand, the amine and hydrogen halide may be added to a reaction vessel at the ratio described above. The amount of the hydrogen halide used is preferably 1 to 50 mol-% and particularly preferably 2 to 20 mol-% as compared with the compound (1).
The reaction is preferably carried out in an alcohol solvent or under no solvents. As the alcohol solvent, e.g. C1-8 lower alcohols, diols or triols are used. C1-8 lower alcohols are particularly preferable. Specially, examples thereof include methanol, ethanol, 1-propanol, 2-propanol, butanol, pentanol, hexanol, 2-ethylhexanol, cyclohexanol, ethyleneglycol, 1,8-octanediol, glycerol and polyethyleneglycol. The amount of the solvent used is preferably 0.5 to 5 times and economically more preferably 0.5 to 2 times the weight of the compound (1). The reaction solvent is suitably selected depending on the physical properties of the compound (1) to be used. If the boiling point of the selected solvent is the reaction temperature or less, the reaction may be carried out under pressurization.
The reaction temperature is preferably 80 to 200xc2x0 C. and particularly preferably 100 to 180xc2x0 C., and the reaction is carried out for a suitable time and, after the reaction is finished, a work-up is carried out according to a usual manner, whereby the compound (2) can be obtained.
The compound (1), the solvent, the amine and the hydrogen halide can be simultaneously introduced and reacted, but the reaction procedure is preferably that, when the reaction temperature is reached, the compound (1) is brought into contact with the catalyst. This procedure includes a method which comprises introducing the compound (1) and the solvent, then adding dropwise a mixed solution of the amine and the hydrogen halide thereto at a predetermined temperature and reacting them and a method which comprises previously introducing the solvent, the amine and the hydrogen halide and then adding dropwise the compound (1) thereto at a predetermined temperature. Any method thereof may be adopted.
[Method 2: The Method for Producing the Compound (2) Obtained from the Compound (3)]
In the compound (3) used as the starting material in the present method, the alkyl group constituting 1-hydroxyalkyl group includes e.g. methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, amyl group, isoamyl group, hexyl group and heptyl group.
This compound (3) can be produced by a publicly known method in the conventional art. For example, it can be obtained by reacting cyclopentanone with an aldehyde or ketone represented by the formula (6): 
wherein R1 and R2 have the same meanings as defined above.
The catalyst used in the present method comprises an amine and hydrogen halide. The amine may be more than enough to form a salt with the hydrogen halide and is not particularly limited but is preferably a weakly basic aromatic amine or heterocyclic aromatic amine. Specifically, it includes those described in the item of Method 1 and is particularly preferably pyridine, picoline or quinoline. The hydrogen halide includes those described in the item of Method 1 and is particularly preferably hydrogen chloride or hydrogen bromide.
The amine and hydrogen halide may be previously formed into a salt to be used. On the other hand, the amine and hydrogen halide may be added to a reaction vessel. The ratio of the amine to the hydrogen halide in the reaction system is preferably that the amine is used in excess. The molar ratio of the amine/the hydrogen halide is preferably from 1/1 to 5/1, more preferably from 1.1/1 to 5/1 and most preferably 1.2/1 to 3/1.
The catalyst comprising the amine and hydrogen halide is preferably added at such a ratio that the amount of the hydrogen halide is 5 to 50 mol-% as compared with the compound (3).
The reaction in the present method in no solvents, but a solvent is preferably used to prevent polymerization as side reaction. The solvent is preferably a polar solvent such as alcohols, diols and triols. Specially, examples of the solvent include those described in the item of Method 1. A C4-8 alcohol is particularly preferable.
The amount of the solvent used is preferably 0.5 to 5 times and economically more preferably 0.5 to 2 times the weight of the compound (3). The solvent is suitably selected in consideration of the physical properties of the compound (3) and the reaction temperature.
With regard to the reaction temperature, from the viewpoint of finishing the reaction in a short time and improving the yield by preventing polymerization of compound (1) and/or (2), the reaction temperature is preferably 100 to 200xc2x0 C. and particularly preferably 130 to 160xc2x0 C. The reaction proceeds at an ordinary pressure but, if the reaction temperature is low, the reaction is preferably carried out under a reduced pressure so that water generated therein can be efficiently distilled away to the outside of the system.
The reaction in the present method is preferably carried out while water generated therein is distilled away. It is preferable in the reaction procedure that, when the reaction temperature is reached, the compound (3) is brought into contact with the catalyst. Because this procedure includes a method for adding dropwise the compound (3) to a mixed solution of the catalyst and the solvent and a method for adding dropwise the catalyst to a mixed solution of the compound (3) and the solvent, any method thereof may be selected.
After the reaction in the present method is finished, a work-up is carried out according to a usual manner, whereby the compound (2) can be obtained.
[Method for Producing the Compound (5)]
By using the compound (2) obtained in Method 1 or 2 described above as the starting material, the compound (5) useful as a perfume material or a biologically active substance can be obtained in a method described in e.g. EP 33604.
Specifically, the compounds (2) and (4) are firstly reacted in the presence of a basic catalyst to obtain a compound represented by the formula (7) (referred to hereinafter as the compound (7)): 
wherein R1, R2 and R3 have the same meanings as defined above.
The compound (4) is preferably reacted at 1 to 5 times and preferably 1.2 to 2 times the mole of the compound (2).
The basic catalyst includes an alkali metal such as sodium and potassium and an alkali metal alkoxide such as a sodium alkoxide and a potassium alkoxide. The catalyst is preferably used in a 0.02- to 0.2-fold molar amount per the compound (2). The solvent is preferably a polar solvent such as alcohols. The reaction temperature is preferably in the range of xe2x88x9210xc2x0 C. to 30xc2x0 C. and more preferably in the range of 0 to 20xc2x0 C.
Then, the obtained compound (7) is reacted with water, whereby the compound (5) can be produced. The reaction is preferably carried out while water is added dropwise to the reaction system in a 1- to 3-fold molar amount per the compound (7). The reaction temperature is preferably in the range of 150 to 220xc2x0 C.
According to the method of the present invention, a 2-alkyl-2-cyclopentenone could be obtained in a high yield even if a solvent is not added in excess. Further, the 2-alkyl- 2-cyclopentenone obtained in this method can be used as the starting material to produce a jasmonate derivative efficiently.